Side effects limit the effectiveness of GLP-1 drugs: what solution can personalization offer?

GLP-1 drugs have taken the industry by storm, but in practice, a significant proportion of patients discontinue treatment, many of them attributing this to intolerable side effects. By integrating digitalization and machine learning, there is an opportunity to provide personalized care to all patients and scale precise dosing with minimal physician involvement, maximizing the efficacy and availability of these drugs.

Originally developed for type 2 diabetes, GLP-1 receptor agonists such as the well-known brands Ozempic, Wegovy, Saxenda, Mounjaro and Zepbound are significantly changing traditional weight loss and having a major impact on conventional approaches. Since the FDA approval of once-weekly injectable GLP-1 semaglutide (Wegovy) for weight management in 2021, the number of new users has increased from 5,717 in 2020 to 120,763 in 2023 – an increase of over 2,000%. As a result of this unexpected increase in demand, ongoing drug shortages are making access to medications difficult for patients who are currently taking or plan to take these drugs for diabetes or weight loss – underscoring the need to implement new strategies to mitigate disruptions in patient care.

Compliance with GLP-1 programs in clinical trials compared to the real world

While clinical trials of GLP-1 for obesity treatment report high one-year persistence rates of over 85%, real-world data paint a very different picture. Clinical trials fail to take into account a patient's individual pharmacokinetic and pharmacodynamic profile. A recent study found that during the first year of GLP-1 therapy for weight loss, only one-third of patients took the drug consistently and only 27% were consistent adherents. This one-year persistence rate is considerably lower than the rates reported in many high-quality clinical trials and even real-world diabetes treatment trials, which show persistence of around 50%. In fact, managing side effects is one of the most important areas of concern for physicians when prescribing these drugs. This discrepancy points to a critical flaw in the one-size-fits-all approach to medicine that often results in suboptimal efficacy and safety.

To achieve significant health benefits and weight loss, patients are recommended to remain on continuous GLP-1 treatment for at least 12 weeks. As with weight maintenance as part of any effective weight management strategy, long-term GLP-1 use requires a healthy diet and resistance training to prevent muscle loss and metabolic decline. Patients who have lost 5% or more of their body weight with GLP-1 treatment have shown noticeable health benefits in improving obesity-related health conditions such as diabetes, high blood pressure, heart disease, liver disease, joint problems and sleep apnea. For example, the SELECT study, a three-year randomized clinical trial (RCT) that also used semaglutide to treat patients with obesity and pre-existing cardiovascular disease but without diabetes, showed a 20% reduction in the risk of heart attack and stroke. Other studies have also investigated the potential of GLP-1 in reducing dementia cases in patients with diabetes and even in the treatment of addiction.

Increasing reports of side effects

Understanding the factors behind the significant decline in persistence and adherence rates in real-world situations is critical not only for patients and healthcare professionals, but also to gain insights into the future of the GLP-1 market. Among factors such as affordability and accessibility, widespread reports of dose-related adverse events stand out. Gastrointestinal problems, including nausea, vomiting and diarrhea, which are particularly common during the dose-escalation phase, can be so severe that patients discontinue treatment voluntarily.

As a result, the initial excitement surrounding GLP-1 is giving way to increasing concerns about the side effects and actual long-term effects of these drugs. This topic was discussed in detail at the recent American Diabetes Association (ADA) 84 meeting.^th Scientific sessions where physicians shared their own experiences prescribing this new drug category and direct patient feedback. Typically, GLP-1, such as semaglutide, is injected once a week, on the same day each week. According to official guidelines, patients start with a low dose (0.25 mg) that is increased every four weeks until the target maintenance dose (2.4 mg) is reached. However, it was interesting to hear that in the real world, this dose escalation schedule is not always used or effective for all patients. Many physicians need to make additional manual medication adjustments to effectively manage side effects and maximize treatment success – including slowing dose escalation, prolonging use of the lowest therapeutic dose for maintenance, and microdosing/intermediate dosing. This tailored dosing approach is also a major topic of discussion for patients on popular social media forums, where thousands seek advice on how best to manage the debilitating side effects without having to stop treatment altogether – “Ozempic” is currently the second largest thread on Reddit.

This situation highlights the urgent need for a patient-centered approach to treatment. There is no one size fits all solution, so why medicine? We need healthcare solutions tailored to our individual needs, as current treatment guidelines result in inconsistent efficacy and increasing safety concerns, and cause avoidable healthcare costs through medication mismanagement and wastage.

Technical solutions to optimize treatment and personalized dosing

Advances in technology and data collection are enabling broader access to personalized care and providing innovative digital health solutions that integrate therapeutic interventions with real-time monitoring devices. This transformative approach can optimize medication effectiveness and enable a higher quality patient experience while supporting healthcare providers.

Digitalization is already having an impact in more established areas of the pharmaceutical industry, and the insights gained can be used to unlock the full potential of emerging markets such as GLP-1. For example, applying a drug-plus-software platform to optimize dosing of a first-line antihypertensive drug led to improved health outcomes and increased medication adherence. In the study, published in the Journal of American Heart Association, real-time data recorded by participants in a dedicated smartphone app was securely transmitted to a physician, enabling personalized adjustments that ultimately resulted in significant reductions in blood pressure and fewer side effects, even in patients who had previously been unable to tolerate standard doses. These findings highlight the potential of personalized dosing and show how digital tools can work with existing and new medicines to optimize patient outcomes and streamline physician engagement, addressing one of the biggest obstacles facing modern medicine – the shortage of healthcare professionals.

There is a clear and unique opportunity to apply dose optimization to GLP-1 to improve persistence and adherence in practice and help patients continue treatment long enough to experience the full benefits, such as positive cardiovascular outcomes. We know that clinicians recognize the need for this and are already taking the necessary actions, but still struggle to find a scalable solution. Combining medicines with proven digital solutions within a single label can facilitate personalization across the GLP-1 market, improving the efficacy of these medicines and reducing side effects. Not only can the pharmaceutical industry use this approach to achieve best-in-class clinical and commercial outcomes, but it also promises to revolutionize disease management by improving patient safety and outcomes by tailoring treatment to individual needs, truly delivering precision care to everyone.

Photo: MF3d, Getty Images

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